Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems.

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PROJECT SUMMARY/ABSTRACT Males are diagnosed with autism spectrum disorder (ASD) at least four times as frequently as females, but the molecular underpinnings of male predominance remain elusive. Serotonergic (5-HT) neurons in the raphe nuclei (RN) extend axonal projections throughout the brain and regulate many essential brain function, including social behaviors. Importantly, abnormal development of the 5-HT system has been described in ASD. 5-HT signaling in the brain differs in males and females, but molecular mechanisms regulating sex-dependent 5-HT synaptic function are largely unknown. The overarching goal of this proposal is to elucidate molecular mechanisms underlying sex-dependent 5-HT synapse development and function, and determine sex-dependent effects of 5- HT on social behavior by focusing on the trans-synaptic molecules Neurexins (Nrxns), a well-accepted risk factor for neurodevelopmental disorders, including ASD. The formation and regulation of synapses are fundamental biological processes in brain development and function. These events require trans-synaptic protein-protein interactions to functionally regulate pre- and postsynaptic structures that determine synaptic function. Neurexins (Nrxns) are presynaptic cell-adhesion molecules and involved in synapse formation and regulation through trans-synaptic protein interactions with postsynaptic adhesion molecules such as neuroligins. Importantly, Nrxn and 5-HT mutant mouse models display deficits in social cognitive behaviors which are reminiscent of ASD. Despite evidence that synapse specification relies on Nrxn function and that appropriate 5-HT signaling impacts social cognitive behaviors, the role of Nrxns in 5-HT synaptic transmission and sex-dependent Nrxn functions is unknown. Our central hypothesis is that the 5-HT system undergoes sex-specific modulation or development. To test this hypothesis, we will identify how Nrxn proteins specifically shape the development and function of the 5- HT system in males and females. This will reveal a previously unexplored 5-HT system architecture that shapes 5-HT neurotransmission and behavior. We will determine i) Nrxn gene(s) important for sex-dependent development of 5-HT release in the RN and hippocampus (Aim 1), ii) Nrxn gene(s) important for sex-dependent development of 5-HT system structure in the hippocampus (Aim 2), and iii) Nrxn gene(s) important for sex- dependent social behavior (Aim 3). We anticipate that our investigation of sex-specific consequences of abnormal 5-HT signaling will profoundly advance our understanding of sex-specific behaviors. Our work should thus contribute to the elucidation of the molecular mechanisms that contribute to the male prevalence of ASD, as well as identify novel therapeutic targets to treat cognitive behavioral deficits in neurodevelopmental and neuropsychiatric disorders such as ASD.